Heretofore, adipose has been broadly classified into white adipose and brown adipose. The white adipose is an organ which stores excessive energy in the form of unilocular lipid droplets in white adipose cells and releases fatty acids according to a nutrition status. Brown adipose cells found in a large amount in the brown adipose have many mitochondria, specifically express a high level of UCP-1 (uncoupling protein-1), and have the property of dissipating energy in the form of heat.
UCP has the function of uncoupling oxidative phosphorylation reaction in the mitochondrial inner membrane and dissipating energy as heat. Recent studies have revealed that the increased expression level of UCP-1, which is typical UCP in brown adipose cells, promotes heat production and consequently increases the consumption of carbohydrate or lipid energy, leading to the inhibition of the fat accumulation, obesity, and diabetes mellitus. Thus, conversion to brown adipose has received attention from the viewpoint of the prevention or amelioration of obesity or metabolic syndrome (Non Patent Literature 1).
Meanwhile, PPARγ (peroxisome proliferator-activated receptor γ), one kind of peroxisome proliferator-activated receptors, is known to prevent or ameliorate diabetes mellitus or insulin resistance through its activation (Non Patent Literature 2). For example, a PPARγ activator pioglitazone or rosiglitazone is utilized as a drug for type 2 diabetes (Non Patent Literature 3).
On the other hand, the Smad family is an intracellular signaling factor which is phosphorylated by stimulation of a TGF-β (transforming growth factor-β) family molecule to transduce the signals thereof to the nucleus. A Smad3-specific Inhibitor SIS3 (specific inhibitor of Smad3) is expected as an agent for prevention or amelioration of tissue fibrosis caused by TGF-β (Non Patent Literature 4). In recent, years, Smad3-deficient mice have shown resistance to dietary obesity and diabetes mellitus, suggesting the possibility that the TGF-β/Smad3 signaling pathway is involved in glucose and energy homeostasis. Thus, the application of a TGF-β control method to prevention or amelioration of obesity and diabetes mellitus has been studied (Non Patent Literature 5). On the other hand, it has also been reported that serum triglyceride levels are rather increased in Smad3-deficient mice, and insulin is also increased (Non Patent Literature 6).
β Adrenaline receptors include 3 subtypes which are classified as β1, β2, and β3. For example, the β3 adrenaline receptor is known to exist mainly in adipose cells, the brain, the gallbladder, the prostate, the bladder, and the intestinal tract and additionally exist in the liver, the stomach, etc. It has been reported as to the β3 adrenaline receptor that stimulation mediated by this receptor causes a lipolysis-promoting action, a heat production-promoting action, a hypoglycemic action, an antihyperlipidemic action, an intestinal motility-inhibiting action, a glucose uptake-promoting action, an antidepressive action, and the like (Patent Literature 1 and Non Patent Literatures 7 and 8).
TGR5 has been reported to exist mainly in skeletal muscle and brown adipose cells and have effects of promoting heat production in adipose tissues and improving energy metabolism by a function of, for example, bile acid as an endogenous ligand of TGR5 (Non Patent Literature 9).    [Patent Literature 1] JP-A-10-33178    [Non Patent Literature 1] Patrick Seale et al., DIABETES, VOL. 58, 1482-1484, 2009    [Non Patent Literature 2] Michael Lehrke et al., Cell 123, 993-999, 2005    [Non Patent Literature 3] Steven M. Watkins et al., Journal of Lipid Research Volume 43, 1809-1817, 2002    [Non Patent Literature 4] Masatoshi Jinnin et al., Mol Pharmacol 63, 597-607, 2006    [Non Patent Literature 5] Hariom Yadav et al., Cell Metabolism 14, 67-79, 2011    [Non Patent Literature 6] Chek Kun Tan et al., Diabetes, 60, 464-476, 2011    [Non Patent Literature 7] David C. Humber et al., J. Med. Chem. 35, 3081-3084, 1992    [Non Patent Literature 8] Masayuki Saito, “Roles of UCP in the regulation of energy expenditure”, the 124th Symposium of the Japanese Association of Medical Sciences, 62-70, 2003    [Non Patent Literature 9] Shinichi Ishii, “Bile acids and their pathophysiological role in metabolic disorders”, Folia, Pharmacol. Jpn., vol. 136, No. 5, November 2010